Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD afflicts 6-10% of the population over age 65 and up to 50% over age 85. It is the leading cause of dementia and the third leading cause of death after cardiovascular disease and cancer. At present, there are no effective treatments for AD and treatment is limited to the use of symptomatic agents such as the cholinesterase inhibitor, donepezil (Aricept®, Pfizer). The total net cost related to AD in the U.S. exceeds $100 billion annually.
AD is characterised pathologically by the presence of specific lesions in the limbic and cortical regions of the brain. These include intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein and the extracellular deposition of fibrillar aggregates of amyloid-beta peptides in the form of amyloid plaques (senile plaques). The major components of amyloid plaques are amyloid-beta (A-beta, Abeta or Aβ) peptides of various lengths (39-42 amino acids). A variant thereof, which is the Aβ1-42 (Abeta1-42, Aβ42) peptide, is believed to be the major pathogenic species in AD brain and can act as a seed for amyloid plaque formation. Another variant is the Aβ1-40 (Abeta1-40, Aβ40) peptide.
The identification of mutations in the beta-Amyloid Precursor Protein (beta-APP, β-APP or APP), Presenilin-1 (PS-1) and Presenilin-2 (PS-2) genes that increase Aβ production and lead to early-onset familial forms of AD have given strong support to the “amyloid cascade hypothesis” of AD (Hardy, 2006 Curr Alzheimer Res. 3(1):71-73; Tanzi and Bertram, 2005 Cell 120, 545) and therapeutic approaches targeting Aβ production. There is emerging data on the role of Aβ peptides in other diseases including, but not limited to Down's syndrome (DS), mild cognitive impairment (MCI), cerebral amyloid angiopathy (CAA), inclusion body myositis (IBM) and age-related macular degeneration. Hence, Aβ lowering agents could be beneficial for the treatment of diverse pathologies in which Aβ peptides are implicated.
Aβ peptides are generated following proteolytic processing of APP. The generation of Aβ peptides is regulated by at least two proteolytic activities referred to as β-site APP cleaving enzyme 1 (BACE-1) and γ-secretase. APP is initially cleaved by BACE-1 at the N-terminus (Met-Asp bond) of the Aβ domain leading to the secretion of soluble APPβ (sAPPβ) and the retention of a 12 kDa membrane-bound carboxy terminal fragment (CTFβ). The latter is subsequently cleaved by γ-secretase to generate Aβ peptides of varying length and an APP intracellular domain (AICD).
It has now become clear that the γ-secretase activity cannot be ascribed to a single protein, but is in fact associated with an assembly of different proteins. The γ-secretase activity resides within a multiprotein complex containing at least four components: a presenilin (PS) heterodimer, nicastrin, anterior pharynx-defective 1 (Aph-1) and presenilin enhancer 2 (Pen-2). The PS heterodimer consists of the amino- and carboxy terminal fragments generated by endoproteolysis of PS and the two aspartates in the catalytic site are at the interface of this heterodimer. It has recently been suggested that nicastrin serves as a γ-secretase-substrate receptor. The functions of the other members of γ-secretase are unknown, but they are all required for activity (De Strooper, 2003 Neuron 38: 9-12; Steiner, 2004. Curr Alzheimer Research 1(3): 175-181). In addition to cleaving APP, γ-secretase is implicated in the intramembrane proteolysis of a number of other proteins including Notch (Haapasalo & Kovacs, 2011 J. Alz. Dis. 25: 3-28).
Due to its pivotal role in the generation of Aβ peptides, γ-secretase is a prime target for the treatment of AD. Various strategies have been proposed for targeting γ-secretase ranging from targeting the catalytic site directly (γ-secretase inhibitors), developing substrate-specific inhibitors (selective γ-secretase inhibitors) and developing modulators of γ-secretase activity (GSMs) (Beher, 2008 Curr Top Med Chem. 8: 34-37, Marjaux et al, 2004. Drug Discovery Today: Therapeutic Strategies, Volume 1, 1-6). Accordingly, a variety of compounds were described that have secretases as targets (Lamer, 2004. Secretases as therapeutics targets in AD: patents 2000-2004. Expert Opin. Ther. Patents 14, 1403-1420). However, due to the fundamental role γ-secretase plays in the intramembrane proteolysis of other proteins, the development of γ-secretase inhibitors was hindered by mechanism-based toxicities associated with inhibition of Notch signalling (Wong et al, 2004 J. Biol. Chem. 279: 12876-12882; Schor, 2011 Ann Neurol. 69: 237-239).
The development of GSMs that have no effect on Notch processing and therefore, should be safer and better tolerated than γ-secretase inhibitors is preferable. Indeed, this finding was supported by biochemical studies in which an effect of certain Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) on γ-secretase was shown (US 2002/0128319; Eriksen (2003) J. Clin. Invest. 1 12, 440). Specifically, these drugs were shown to shift γ-secretase cleavage of APP away from the amyloidogenic Aβ42 site towards cleavage at the Aβ37 and Aβ38 sites, such that the decrease in Aβ42 was accompanied by an increase in the shorter, less amyloidogenic Aβ peptides. No effect on Notch processing was observed. Potential limitations for the use of NSAIDs to prevent or treat AD include their inhibition of cyclooxygenase (COX) enzymes, which can lead to unwanted side effects, and their low CNS penetration (Peretto et al, 2005, J. Med. Chem. 48, 5705-5720). NSAID derivatives such as R-flurbiprofen (Flurizan™) that are devoid of COX inhibitory activity but retain the Aβ42 lowering activity were subsequently identified and progressed to clinical trials (Wilcock et al, 2008 Lancet Neurol. 7: 483-493). However, R-flurbiprofen (Flurizan™) failed to show efficacy in a Phase 3 clinical trial (Green et al, 2009 JAMA 302: 2557-2564) due to its weak potency and poor brain penetration. Other patent literature on GSMs include WO-2009/032277 which relates to heterocyclic compounds useful as γ-secretase modulators and WO-2010/083141, WO-2011/086098 which relate to bicyclic compounds for the reduction of beta-amyloid production.
There is a strong need for novel compounds which modulate γ-secretase activity thereby opening new avenues for the treatment of AD. It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. It is accordingly an object of the present invention to provide such novel compounds.